The invention relates to a method for strengthening a vessel wall e.g., by irradiation with an energy source, or by inducing injury to the vessel wall, such that the injury initiates a cascade of events leading to fibrosis and a thickening of the vessel wall. In addition to an energy source, a photoactivable agent can also be used such that the energy activates the photoactivable agent which causes structural changes in the vessel wall. More specifically, the invention relates to treating aneurysms using UV radiation with a psoralen compound.
There are two basic types of blood vessels, arteries and veins, which can be distinguished by their structural components. Arteries and veins both have several distinct layers which are arranged coaxially. In arteries, the layers include an inner coat or endothelial layer (intima), an internal elastic lamina, a middle layer (media), and an outer layer (adventitia). Like arteries, veins include an inner layer (intima), a middle layer (media) and an outer layer (adventitia), but the layers are not as thick as in arteries, and provide less structural rigidity.
Both arteries and veins are elastic, and are capable of limited deformation in response to pressure changes. When a diseased blood vessel is exposed to hypertension, dilation may occur at various localized regions. Typically these dilatations are produced at the region in the vessel wall which is weakest, whether inherently or as a result of disease or trauma. As the dilatation progresses, a more pronounced widening or sac, called an aneurysm, is produced, which may burst. A large aneurysm can form clots secondary to a reduction in blood flow in the aneurysmal sac. These clots may emobilize and block distal arteries.
Arteriosclerosis and cystic medial necrosis are two common causes of aneurysms of the thoracic and abdominal aorta. Thoracic aneurysms commonly compress and impact surrounding body structures as they expand. They may impact into the lungs, the spinal column, or the gastrointestinal tract.
Berry aneurysms are congenital defects which occur in cerebral arteries, most commonly at the junctions of vessels in the circle of Willis. These aneurysms appear to be related to defects in the muscular coat of the vessels. Rupture is common, resulting in intracranial hemorrhage.
Other aneurysms include aortic aneurysms, especially abdominal aortic aneurysms (AAA), which are characterized by transmural aortic wall degeneration leading to dilatation, progressive growth, and eventual rupture.
Treatment of aneurysms typically involves either surgical intervention, such as in thoracic or abdominal aneurysms, or coil ablation, such as in aneurysms of the brain. Excision of the aneurysm, and anastomosis of the vessel may be performed, often using a replacement vessel or an artificial prosthesis. Alternatively, a supporting structure such as a stent or other intravascular device may be implanted into the vessel to relieve stress. Examples of stents, include those disclosed in U.S. Pat. No. 4,655,771 issued to Wallsten et al. With the stent positioned at the treatment site, the stent can be radially expanded into a conforming surface in contact with a blood vessel wall. The stents may also be covered with a film or a sheath such as, polytetrafluoroethylene (PTFE) as described in U.S. Pat. No. 5,788,626 to Thompson, et al.
Prostheses used to treat aneurysms are also described in, for example, U.S. Pat. No. 4,681,110 issued to Wiktor et al. Wiktor et al. discloses a flexible tubular liner that is inserted into the aorta to treat aortic aneurysms. The liner has flexible plastic strands designed to elastically expand against the aneurysm and to direct blood flow past the aneurysm.
While these methods achieve the general goal of reducing fatality, these methods have a drawback in that the aneurysm remains a weak area in the blood vessel wall. Mohr et al. in U.S. Pat. No. 5,921,954 describe treating aneurysms using hardening and softening agents, (e.g. collagen), which are applied at the site of the aneurysm. A radio frequency energy is then used to harden the agent and cover the weak region of the blood vessel wall.
Prophylactic methods are used to prevent the formation of aneurysms and rely on reducing the blood pressure, in an effort to reduce mechanical stress on the vasculature. These methods involve using drugs which can have undesirable side effects, e.g., cause kidney or liver damage.
Drugs, such as tetracyclines have been used to prevent abnormal vascular dilation, as described in U.S. Pat. No. 5,834,449 issued to Thompson et al. The tetracycline compounds protect the elastic fibers of the media by selectively inhibiting the elastolytic activity in this region thereby preventing its expansion.
While these methods are effective in treating aneurysms, these methods do not improve the overall structure of the blood vessel which still remains weak at the site of the aneurysm and may still be susceptible to rupture. Accordingly, one purpose of this invention is to provide a method of strengthening a blood vessel.
The invention pertains to methods for strengthening a vessel wall of a subject by thickening or increasing the strength of at least one layer of the blood vessel wall by inducing fibrosis. Strengthening a vessel wall may be accomplished by either applying energy alone, or by applying energy with agents, such as compounds and therapeutic agents that induce fibrosis. It has been discovered that certain photoactive compounds, such as psoralen agents play a role in regulating the cell proliferation in the adventitial layer of the blood vessel. This invention is based at least, in part, on the surprising discovery that blood vessel walls treated with a psoralen agent, such as 8-methoxypsoralen, (8-MOP) (available commercially as Uvadex, an injectable formulation from Johnson and Johnson, Exton, Penn.), and subsequently irradiated with light, e.g., ultra-violet A (UVA) irradiation, will exhibit fibrosis, especially in the adventitial layer.
The vessel wall can be strengthened by altering the cellular and molecular processes to thicken one or more layers of the vessel wall, for example, by inducing fibrosis in the adventitia of a blood vessel, thereby enabling it to return to a more normal, less weakened state. The method of the invention can be used to treat aneurysms by inducing the fibrosis in the adventitial layer of a blood vessel.
Accordingly, in one aspect, the invention pertains to a method for strengthening the vessel wall of a subject by identifying a region of weakness in a vessel wall, the region of weakness comprising at least one target layer; and applying energy to the region of weakness in an amount effective to induce fibrosis in a target layer, to thereby strengthen the vessel wall. The region of weakness can be identified using techniques such as ultrasound analysis, X-ray analysis, computerized tomography, magnetic resonance imaging (MRI), or angiography.
Energy can be applied to the region of weakness by irradiating the region of weakness with X-ray irradiation in an amount effective to induce fibrosis in a target layer.
Other forms of energy applied in an amount effective to induce fibrosis in a target layer also include, but not limited to, UV irradiation, IR irradiation, microwave irradiation, heat irradiation and RF irradiation.
The method can further comprise, administering a therapeutically effective amount of an agent to a subject, such that the agent is taken up by at least one target layer of the vessel wall. In one embodiment, the agent can be a photoactivatable agent, such that the photoactivatable agent is activated upon irradiation to induce fibrosis in a target layer.
In another aspect, the invention pertains to a method for strengthening a vessel wall of a subject by administering a therapeutically effective amount of a photoactivatable agent to a subject, such that the agent is taken up by at least one layer of the vessel wall, and irradiating a target region of the vessel wall, such that the photoactivatable agent is activated to strengthen the vessel wall.
The photoactivatable agent can be administered using any known methods for administrating therapeutic agents, for example, systemic, local, oral administration, and the like. In one embodiment, the administering step comprises systemically administering the photoactivatable agent. In another embodiment, the administering step comprises locally administering the photoactivatable agent.
The photoactivatable agent can be any agent that is activated by light energy. In the activated state, the photoactivatable agent is capable of causing changes in the cellular and molecular processes in the localized microenvironment, e.g., structural changes by altering cell proliferation in at least one layer of the vessel resulting in a change of thickness in the layer. In one embodiment, the photoactivatable agent is a psoralen agent or a derivative thereof.
The photoactivatable agent can be activated using a light source in a variety of ways. Photoactivation can occur by irradiating a target region internally by a light source applied at the target region in-vivo. Photoactivation may also occur by irradiating the target region using an external light source. The entire area of the subject can be irradiated externally or, a desired localized area can be irradiated externally. In one embodiment, the irradiating step comprises irradiating the target region internally using a light delivery catheter. In another embodiment, the irradiating step comprises irradiating the target region using a light delivery catheter without occluding fluid flow. In yet another embodiment, the irradiating step comprises irradiating the target region externally using an external light delivery source. In a preferred embodiment, the irradiating step comprises irradiating the target region with UV light, preferably with light having a wavelength of about 240 to 370 nanometers. In another embodiment, the irradiating step comprises irradiating the target region to increase the area of the vessel wall outer layer, e.g., the adventitia.
In another aspect, the invention pertains to a method for increasing the adventitial mass of a blood vessel wall within a target region by administering a therapeutically effective amount of a photoactivatable agent to a subject, such that the agent is taken up by the adventitial layer, and irradiating a target region of the blood vessel wall so that the photoactivatable agent is activated to increase the adventitial volume.
In another aspect, the invention pertains to a method for treating an aneurysm by increasing the adventitial volume of a blood vessel by administering a therapeutically effective amount of a photoactivatable agent to a subject, such that the agent is taken up by the adventitial region of the blood vessel, and irradiating the site of the aneurysm so that the photoactivatable agent increases the adventitial volume.
Strengthening a vessel wall of a subject by increasing the volume of at least one layer of the blood vessel wall may also be attained by irradiating the target region with light energy of a specific wavelength. The irradiation alone can be sufficient to activate cellular and molecular process that result in an increase in a vessel wall layer.
Accordingly, in another aspect, the invention pertains to a method for strengthening a vessel wall of a subject by irradiating a target region with UVC irradiation, so that the UVC irradiation induces a structural change in at least one layer of the vessel wall. Additionally, the invention pertains to a method for increasing the adventitial volume of a blood vessel wall by irradiating the target region with UVC irradiation, and more specifically, to a method for treating an aneurysm by increasing the adventitial volume of a blood vessel by irradiating the site of the aneurysm with UVC irradiation.